title: Interleukin-33/ST2 axis promotes breast cancer growth and metastases by facilitating intratumoral accumulation of immunosuppressive and innate lymphoid cells.
abstract: The role of IL-33/ST2 pathway in antitumor immunity is unclear. Using 4T1 breast cancer model we demonstrate time-dependent increase of endogenous IL-33 at both the mRNA and protein levels in primary tumors and metastatic lungs during cancer progression. Administration of IL-33 accelerated tumor growth and development of lung and liver metastases, which was associated with increased intratumoral accumulation of CD11b(+) Gr-1(+) TGF-β1(+) myeloid-derived suppressor cells (MDSCs) that expressed IL-13α1R, IL-13-producing Lin(-) Sca-1(+) ST2(+) innate lymphoid cells (ILCs) and CD4(+) Foxp3(+) ST2(+) IL-10(+) Tregs compared to untreated mice. Higher incidence of monocytic vs. granulocytic MDSCs and plasmocytoid vs. conventional dendritic cells (DCs) was present in mammary tumors of IL-33-treated mice. Intratumoral NKp46(+) NKG2D(+) and NKp46(+) FasL(+) cells were markedly reduced after IL-33 treatment, while phosphate-buffered saline-treated ST2-deficient mice had increased frequencies of these tumoricidal natural killer (NK) cells compared to untreated wild-type mice. IL-33 promoted intratumoral cell proliferation and neovascularization, which was attenuated in the absence of ST2. Tumor-bearing mice given IL-33 had increased percentages of splenic MDSCs, Lin(-) Sca-1(+) ILCs, IL-10-expressing CD11c(+) DCs and alternatively activated M2 macrophages and higher circulating levels of IL-10 and IL-13. A significantly reduced NK cell, but not CD8(+) T-cell cytotoxicity in IL-33-treated mice was observed and the mammary tumor progression was not affected when CD8(+) T cells were in vivo depleted. We show a previously unrecognized role for IL-33 in promoting breast cancer progression through increased intratumoral accumulation of immunosuppressive cells and by diminishing innate antitumor immunity. Therefore, IL-33 may be considered as an important mediator in the regulation of breast cancer progression.
authors.affiliation: Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Jovanovic
authors.forename: Nada N
authors.initials: NN
authors.lastname: Pejnovic
authors.forename: Gordana D
authors.initials: GD
authors.lastname: Radosavljevic
authors.forename: Jelena M
authors.initials: JM
authors.lastname: Pantic
authors.forename: Marija Z
authors.initials: MZ
authors.lastname: Milovanovic
authors.forename: Nebojsa N
authors.initials: NN
authors.lastname: Arsenijevic
authors.forename: Miodrag L
authors.initials: ML
authors.lastname: Lukic
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D048708:Cell Growth Processes / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D018123:Receptors, Interleukin
keywords: 4T1 mammary carcinoma; IL-33; NK cells; T regs; dendritic cells; innate lymphoid cells; myeloid-derived suppressor cells